Octacyclodepsipeptides having an endoparasiticidal action

ABSTRACT

The present invention relates to compounds of the general formula (I)                    
     in which 
     R 1  and R 12  represent the same or different radicals selected from the group of C 2-9 -alkyl, C 1-8 -halogen-alkyl, C 3-6 -cycloalkyl, aralkyl or aryl, 
     R 3  to R 10  represent the same or different radicals selected from the group of hydrogen, C 1-5 -alkyl which may optionally be substituted by hydroxyl, alkoxy, carboxyl, carboxamide, imidazolyl, indolyl, guanidino, thio- or thioalkyl, and represent aryl, alkylaryl or heteroarylmethyl which are optionally substituted by halogen, hydroxyl, alkyl, alkoxy, nitro or a —NR 13 R 14  group in which R 13  or R 14  independently from each other represent hydrogen or alkyl or together with the adjoining nitrogen atom form a  5, 6  or  7 -membered ring which is optionally interrupted by O, S or N and which is optionally substituted by C 1-4 -alkyl, 
     R 2  and R 11  represent the same of different radicals selected from the group of C 1-4 -alkyl, 
     and stereoisomers thereof, to processes for their preparation and to their use as endoparasiticides.

The present invention relates to new octacyclodepsipeptides and to aplurality of processes for their preparation and their use asendoparasiticides.

European Published Specification 0 382 173 discloses a cyclicdepsipeptide with the designation PF 1022. The compound possesses ananthelmintic action. At low application rates, however, the activity insome cases leaves something to be desired.

The present invention relates, then, to:

1. Compounds of the general formula (I)

in which

R¹ and R¹² represent the same or different radicals selected from thegroup of C₂₋₉-alkyl, C₁₋₈-haloqenoalkyl, C₃₋₆-cycloalkyl, aralkyl oraryl,

R³ to R¹⁰ represent the same or different radicals selected from thegroup of hydrogen, C₁₋₅-alkyl which may optionally be substituted byhydroxyl, alkoxy, carboxyl, carboxamide, imidazolyl, indolyl, guanidino,thio- or thioalkyl, and represent aryl, alkylaryl or heteroarylmethylwhich are optionally substituted by halogen, hydroxyl, alkyl, alkoxy,nitro or a —NR¹³R¹⁴ group in which R¹³ or R¹⁴ independently from eachother represent hydrogen or alkyl or together with the adjoiningnitrogen atom form a 5, 6 or 7-membered ring which is optionallyinterrupted by O, S or N and which is optionally substituted byC₁₋₄-alkyl,

R² and R¹¹ represent the same of different radicals selected from thegroup of C₁₋₄-alkyl,

2. Process for the preparation of the compounds of the formula (I)

in which

R¹ and R¹² represent the same or different radicals from the group ofC₂₋₉-alkyl, C₁₋₈-halogenoalkyl, C₃₋₆-cycloalkyl, aralkyl or aryl,

R³ to R¹⁰ represent the same of different radicals selected from thegroup of hydrogen, C₁₋₅-alkyl which may which may optionally besubstituted by hydroxyl, alkoxy, carboxyl, carboxamide, imidazolyl,indolyl, guanidino, thio- or thioalkyl, and represent aryl, alkylaryl orheteroarylmethyl which are optionally substituted by halogen, hydroxyl,alkyl, alkoxy, nitro or a —NR¹³R¹⁴ group in which R¹³ or R¹⁴independently from each other represent hydrogen or alkyl or togetherwith the adjoining nitrogen atom form a 5, 6 or 7-membered ring which isoptionally interrupted by O, S or N and which is optionally substitutedby C₁₋₄-alkyl,

R² and R¹¹ represent the same of different radicals selected from thegroup of C₁₋₄-alkyl,

open-chain octadepsipeptides of the formula (II)

in which

R¹ to R¹² have the meaning given above are cyclized

in the presence of a diluent and in the presence of a coupling reagent.

3. Open-chain octadepsipeptides of the formula (II)

in which

R¹ to R ¹² have the meaning given above.

4. Process for the preparation of the open-chain octadepsipeptides ofthe formula (II)

in which

R¹ to R¹² possess the meaning given above,

characterized in that compounds of the formula (III)

in which

A represents benzyl and

R¹ to R¹² possess the meaning given above

are subjected in the presence of a diluent and a catalyst tohydrogenolysis.

5. Compounds of the formula (III)

in which

A represents benzyl and

R¹ to R¹² possess the meaning given above.

6. Process for the preparation of the compounds of the formula (III)

in which

A represents benzyl and

R¹ to R¹² possess the meaning given above,

characterized in that compounds of the formula (IV)

in which

A represents benzyl and

B represents tert.-butoxy, and

R¹ to R¹² possess the meaning given above,

are hydrolysed in the presence of a diluent and a protic acid.

7. Compounds of the formula (IV)

in which

A represents benzyl and

B represents tert.-butoxy, and

R¹ to R¹² have the meaning given above.

8. Process for the preparation of the compounds of the formula (IV)

in which

A represents benzyl and

B represents tert.-butoxy, and

R¹ to R¹² have the meaning given above,

characterized in that tetradepsipeptides of the formula (V)

in which

A represents benzyl and

Z represents OH or Cl, and

R¹, R², R³, R⁴, R⁵ and R¹⁰ have the meaning given above,

and tetradepsipeptides of the formula (VI)

in which

D represents hydrogen and

B represents tert.-butoxy, and

R⁶, R⁷, R⁸, R⁹, R¹¹ and R¹² have the meaning given above,

are condensed in the presence of a diluent and a suitable couplingreagent.

9. Tetradepsipeptides of the formula (V)

in which

A represents benzyl and

Z represents OH or Cl, and

R¹, R², R³, R⁴, R⁵ and R¹⁰ have the meaning given above.

10. Tetradepsipeptides of the formula (VI)

in which

D represents hydrogen and

B represents tert.-butoxy, and

R⁶, R⁷, R⁸, R⁹, R¹¹ and R¹² possess the meaning given above,

11. Process for the preparation of the tetradepsipeptides of the formula(V)

in which

A represents benzyl and

Z represents OH or Cl, and

R¹, R², R³, R⁴, R⁵ and R¹⁰ have the meaning given above,

characterized in that tetradepsipeptides of th1e formula (VII)

in which

A represents benzyl and

B represents tert.-butoxy, and

R¹, R2, R³, R⁴, R⁵ and R¹⁰ have the meaning given above,

are hydrolysed in the presence of a diluent and a protic acid.

12. Process for the preparation of the tetradepsipeptides of the formula(VI)

in which

D represents hydrogen and

B represents tert.-butoxy, and

R⁶, R⁷, R⁸, R⁹, R¹¹ and R¹² have the meaning given above,

characterized in that tetradepsipeptides formula (VII)

in which

A represents benzyl and

B represents tert.-butoxy, and

R¹, R², R³, R⁴, R⁵ and R¹⁰ possess the meaning given above,

are subjected in the presence of a diluent and a catalyst tohydrogenolysis.

13. Tetradepsipeptides of the formula (VII)

in which

A represents benzyl and

B represents tert.-butoxy, and

R¹, R2, R³, R⁴, R⁵ and R¹⁰ have the meaning given above.

14. Process for the preparation of the tetradepsipeptides of the formula(VII)

in which

A represents benzyl and

B represents tert.-butoxy, and

R¹, R², R³, R⁴, R⁵ and R¹⁰ possess the meaning given above,

characterized in that didepsipeptides of the formula (VIII)

in which

A represents benzyl and

Z represents OH or Cl, and

R¹, R³ and R¹⁰ possess the meaning given above and didepsipeptides ofthe formula (IX)

in which

D represents hydrogen and

B represents tert.-butoxy, and

R², R⁴ and R⁵ possess the meaning given above,

are condensed in a diluent in the presence of a suitable couplingreagent.

15. Didepsipeptides of the formula (VIII)

in which

A represents benzyl and

Z represents OH or Cl, and

R¹, R³ and R¹⁰ possess the meaning given above.

16. Didepsipeptides of the formula (IX)

in which

D represents hydrogen and

B represents tert.-butoxy, and

R², R⁴ and R⁵ possess the meaning given above.

17. Process for the preparation of didepsipeptides of the formula (VIII)

in which

Z represents OH or Cl and

A represents benzyl, and

R¹, R³ and R¹⁰ possess the meaning given above. The processes arecharacterized in that a compound of the formula (X)

in which

A represents benzyl and

B represents tert.-butoxy, and

R¹, R³ and R¹⁰ possess the meaning given above and a diluent arehydrolysed in the presence of a protic acid.

18. Process for the preparation of didepsipeptides of the formula (IX)

in which

D represents hydrogen and

B represents tert.-butoxy, and

R², R⁴ and R⁵ possess the meaning given above, characterized in thatcompounds of the formula (XI)

in which

A represents benzyl and

B represents tert.-butoxy, and

R², R⁴ and R⁵ possess the meaning given above,

are subjected in the presence of a diluent and a catalyst tohydrogenolysis.

19. Didepsipeptides of the formula (X)

in which

A represents benzyl and

B represents tert.-butoxy, and

R¹, R³ and R¹⁰ possess the meaning given above.

20. Didepsipeptides of the formula (XI)

in which

A represents benzyl and

B represents tert.-butoxy, and

R², R⁴ and R⁵ possess the meaning given above.

21. Process for the preparation of didepsipeptides of the formula (X)

in which

A represents benzyl and

B represents tert.-butoxy, and

R¹, R³ and R¹⁰ possess the meaning given above,

characterized in that an aminocarboxylic acid of the formula (XII)

in which

A represents benzyl and

R¹ and R¹⁰ possess the meaning given above,

in the form of an alkali metal salt thereof, preferably of its caesiumsalt, and an α-halogenocarboxylic acid of the formula (XIII)

in which

X represents Cl or Br and

B represents tert.-butoxy, and

R³ possesses the meaning given above,

are coupled in the presence of a diluent.

22. Process for the preparation of didepsipeptides of the formula (XI)

in which

A represents benzyl and

B represents tert.-butoxy, and

R², R⁴ and R⁵ possess the meaning given above,

characterized in that an aminocarboxylic acid of the formula (XIV)

in which

A represents benzyl and

R¹ and R¹⁰ possess the meaning given above,

in the form of an alkali metal salt thereof, preferably of its caesiumsalt, and an α-halogenocarboxylic acid of the formula (XV)

in which

X represents Cl or Br and

B represents tert.-butoxy, and

R⁵ possesses the meaning given above,

are coupled in the presence of a diluent.

Finally it has been found that the new octacyclodepsipeptides of theformula (I) and their acid addition salts and metal salt complexespossess very good endoparasiticidal, especially anthelmintic, propertiesand can be employed preferably in the veterinary sector. Surprisingly,the substances according to the invention exhibit, in the control ofworm diseases, a distinctly better activity than the previously knowncompound having a similar constitution and the same approach of action.

In the general formulae, alkyl denotes straight-chain or branched alkylhaving preferably 1 to 9 carbon atoms, particularly preferably 1 to 5,and very particularly preferably 1 to 4, carbon atoms. The following maybe mentioned by way of example: methyl, ethyl, n- and i-propyl, n-, i-,s- and t-butyl, pentyl, hexyl and octyl which are optionallysubstituted.

In the general formulae alkenyl denotes straight-chain or branchedalkenyl having preferably 2 to 20, particularly 2 to 8 carbon atoms. Thefollowing may be mentioned by way of example: ethenyl, propenyl-(1),propenyl-(2), butenyl-(3) which are optionally substituted.

In the general formulae cycloalkyl denotes mono-, bi- or tri- cycliccycloalkyl having preferably 3 to 10, particularly 3, 5 or 6 ring carbonatoms. The following may be mentioned by way of example: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl which are optionallysubstituted.

Alkoxy in the general formulae is straight-chain or branched alkoxyhaving preferably 1 to 6, in particular 1 to 4, carbon atoms. Methoxy,ethoxy, propoxy, butoxy and their isomers, such as, for example,i-propoxy, and i-, s- and t-butoxy, may be mentioned by way of example,and may be substituted.

Alkylthio in the general formulae is straight-chain or branchedalkylthio having preferably 1 to 6, particularly preferably 1 to 4,carbon atoms, for example optionally substituted methylthio, ethylthio,propylthio, butylthio, pentylthio and their isomers, such as, forexample, i-propylthio, i-, s- and t-butylthio. Halogenoalkyl in thegeneral formulae has 1 to 4, particularly 1 or 2 carbon-atoms and 1 to9, particularly 1 to 5 same or different halogen atoms. As halogen atomsare mentioned fluorine, chlorine. The following may be mentioned by wayof example trifluoromethyl, chloro-difluoromethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, perfluoro-t-butyl.

Aryl in the general formulae is aryl having preferably 6 or 10 carbonatoms in the aryl moiety. Unsubstituted or substituted phenyl ornaphthyl, in particular phenyl, may be mentioned as being preferred andmay be substituted.

Arylalkyl in the general formulae is optionally substituted in thealkyl- or in the aryl part, it has preferably 6 or 10, particularly 6carbon atoms in the aryl part, mention being made of naphthyl andphenyl, very particularly mentioned is phenyl, in the alkyl part 1 to 4carbon atoms, particularly 1 or 2 carbon atoms may be mentioned. Benzylor phenethyl may be mentioned by way of example.

Heteroaryl in the general formulae is preferably a 5 to 7-memberedheteroaromatic, optionally benzo-fused ring which contains one or morehetero atoms, preferably 1 to 3 identical or different hetero atoms.Preferred hetero atoms which may be mentioned are oxygen, sulphur andnitrogen. The following may be mentioned as particularly preferred forheteroaryl: pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl,thienyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, isothiazolyl,pyrrolyl, piperazinyl, triazinyl, oxazinyl, oxepinyl, thiepinyl,diazepinyl, thiazolyl, thiadiazolyl, oxadiazolyl, oxazolyl, quinolyl,isoquinolyl, benzoxazolyl, benzothiazolyl and benzimidazolyl. Theheteroaryl ring can itself be substituted.

In the general formulae optionally substituted radicals may carry one ormore, preferably 1 to 3, particularly 1 to 2 same or differentsubstituents. The following substituents may be mentioned as examples:

Alkyl with preferably 1 to 4 particularly 1 to 2 carbon atoms, methyl,ethyl, n- and i-propoyl, n-, i- and t-butyl are named as examples;alkoxy with preferably 1 to 4 particularly 1 to 2 carbon atoms, methoxy,ethoxy, n- or i-propoxy, n-, i- or t-butoxy are named as examples;alkylthio with preferably 1 to 4 particularly 1 to 2 carbon atoms,methylthio, ethylthio, n- or i-propylthio, n-, i- or t-butylthio arenamed as examples; alkylsulfinyl or alkylsulfonyl with preferably 1 to 4particularly 1 to 2 carbon atoms like methylsulfinyl, methylsulfonyl,ethylsulfinyl, ethylsulfonyl; arylsulfonyl with 6 to 10 carbon atoms inthe aryl part like phenylsulfonyl; halogenoalkyl, halogenoalkoxy,halogenoalkylthio, halogenoalkylsulphinyl and/or halogenoalkylsulphonyl(having in each case preferably 1 to 4, in particular 1 or 2, carbonatoms and in each case 1 to 6, in particular 1 to 3, identical ordifferent halogen atoms, in particular fluorine and/or chlorine atoms),trifluormethyl, difluormethyl, trifluormethylsulfinyl,trifluormethylsulfonyl, perfluor n, s, t-butylsulfonyl may be mentionedby way of example. Further substituents which may be mentioned arehydroxy, halogen preferably fluorine, chlorine, cyano, nitro, amino,formimino

mono- or dialkylamino having 1 or 2 alkyl groups, each of which can bestraight-chain or branched and contain preferably 1 to 5, in particular1 to 4 and particularly preferably 1 to 3, carbon atoms, mention beingmade of methyl, ethyl and n- and i-propyl; dimethylamino, diethylamino,di-n-propylamino and di-i-propylamino may be mentioned by way ofexample; further substituents which may be mentioned are acyl, aryl,aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy which may besubstituted themselves by one of the above mentioned substituents.

It is preferred to employ compounds of the formula (I) in which

R¹ and R¹², independently of one another, represent ethyl, propyl, butylor phenyl which is optionally substituted by halogen, C₁₋₄-alkyl, OH,C₁₋₄-halogenoalkyl, C₁₋₄-alkoxy, C₁₋₄-halogenoalkoxy, and represent CF₃,benzyl or phenylethyl, each of which may optionally be substituted bythe radicals given above;

R³ to R¹⁰, independently of one another, represent hydrogen, C₁₋₅-alkylwhich is optionally by C₁₋₄-alkoxy, carboxamide, imidazolyl, indolyl,thio and C₁₋₄-thioalkyl,

alkylaryl or heteroarylmethyl which are optionally substituted byhalogen, hydroxyl, alkyl, alkoxy, nitro or a —NR¹³R¹⁴ group in which R¹³or R¹⁴ independently from each other represent hydrogen or alkyl ortogether with the adjoining nitrogen atom form a 5, 6 or 7-membered ringwhich is optionally interrupted by O, S or N and which is optionallysubstituted by C₁₋₄-alkyl,

R² and R¹¹, independently of one another, represent methyl, ethyl,iso-propyl, propyl.

Particularly preferred compounds of the formula (I) are those in which

R¹ and R¹², independently of one another, represent ethyl, propyl,iso-propyl, butyl or phenyl,

R³ to R¹⁰, independently of one another, represent hydrogen, C₁₋₅-alkylwhich may optionally be substituted by methoxy, ethoxy, imidazolyl,indolyl, guanidino or methylthio, ethylthio, and phenyl, benzyl,phenylethyl or heteroarylmethyl,

which are optionally substituted by halogen, hydroxyl, alkyl, alkoxy,nitro or a —NR¹³R¹⁴ group in which R¹³ or R¹⁴ independently from eachother represent hydrogen or alkyl or together with the adjoiningnitrogen atom form a 5, 6 or 7-membered ring which is optionallyinterrupted by O, S or N and which is optionally substituted byC₁₋₄-alkyl,

R² and R¹¹, independently of one another, represent methyl, ethyl,propyl or butyl.

In Process 2, octadepsipeptides are cyclized in the presence of diluentsand suitable coupling reagents.

Suitable coupling reagents are all compounds which are suitable forlinking an amide bond (cf. e.g.: Houben-Weyl, Methoden der organischenChemie, volume 15/2; Bodenzky et al., Peptide Synthesis 2nd ed., Wileyand Sons, New York 1976).

The following methods are preferably considered, the active ester methodwith pentafluorophenol (PfP), N-hydroxy-succinimide,1-hydroxybenzotriazole, coupling with carbodiimides such asdicyclohexylcarbodiimide orN′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EBC) and the mixedanhydride method or coupling with phosphonium reagents such asbenzotriazol-1-yl-oxy-tris(dimethylaminophosphonium) hexafluorophosphate(BOP), bis-(2-oxo-3-oxazolidinyl)-phosphonium acid chloride (BOP-Cl) orwith phosphonate reagents such as diethyl cyanophosphonate (DEPC) anddiphenylphosphoryl azide (DPPA).

Particular preference is given to the coupling withbis(2-oxo-3-oxazolidinyl)-phosphonium acid chloride (BOP-Cl) andN′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC) in the presence of1-hydroxybenzotriazole (HOBt).

The reaction is carried out at temperatures from 0-150° C., preferablyat 20-100° C., particularly preferably at room temperature.

Suitable diluents are all inert organic solvents. These include, inparticular, aliphatic and aromatic, optionally halogenated hydrocarbonssuch as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine,ligroin, benzene, toluene, methylene chloride, ethylene chloride,chloroform, carbon-tetrachloride, chlorobenzene and o-dichlorobenzene,also ethers such as diethyl- and dibutyl ether, glycol dimethyl etherand diglycol dimethyl ether, tetrahydrofuran and dioxane, furthermoreketones such as acetone, methyl ethyl, methyl isopropyl and methylisobutyl ketone, in addition esters such as methyl acetate and ethylacetate, also nitriles, for example acetonitrile and propionitrile,benzonitrile, glutaronitrile, moreover amides, for exampledimethylformamide, dimethylacetamide and N-methylpyrrolidone, anddimethyl sulphoxide, tetramethylene sulphone and hexamethylphosphorictriamide.

The cyclization is carried out in the presence of a base.

Suitable bases are inorganic and organic bases. Bases which may bementioned are alkali metal and alkaline earth metal hydroxides,carbonates, hydrogen carbonates, alcoholates, and also amines such as,in particular, tertiary amines e.g. trimethylamine, triethylamine,N-methylmorpholine, pyridine, picolines, N-ethylpyrrolidine,diazabicyclo[4.3.0]-undecene(DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), diazabicyclo[3.2.0]nonene (DBN), ethyl diisopropylamine.

The compounds of the formulae (II) and the bases are employed in a ratioof from 1:1 to 1:1.5 with respect to one another. An approximatelyequimolar ratio is preferred.

After reaction has taken place, the diluent is distilled off and thecompounds of the formula (I) are purified in a conventional manner, forexample by chromatography.

The reaction according to Process 4 is carried out using hydrogenatingagents.

The preferred hydrogenating agent which may be mentioned is hydrogen inthe presence of the conventional hydrogenation catalysts, for exampleRaney nickel, palladium and platinum.

The process is preferably carried out using diluents. Suitable diluentsin this context are practically all inert organic solvents. Theseinclude, preferably, aliphatic and aromatic, optionally halogenatedhydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleumether, benzine, ligroin, benzene, toluene, xylene, methylene chloride,ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene ando-dichlorobenzene, ethers, such as diethyl and dibutyl ether, methyltert.-butyl ether, glycol dimethyl ether and diglycol dimethyl ether,tetrahydrofuran and dioxane, esters such as methyl acetate and ethylacetate, nitriles, for example acetonitrile and propionitrile, amides,for example dimethylformamide, dimethylacetamide andN-methyl-pyrrolidone and dimethyl sulphoxide, tetramethylene sulphoneand hexamethylphosphoric triamide; and also alcohols such as methanol,ethanol, propanol, isopropanol, butanol, isobutanol, sec.-butanol,tert.-butanol, pentanol, isopentanol, sec.-pentanol and tert.-pentanol,and water.

The reaction temperatures in the process according to the invention canbe varied over a relatively wide range. The temperatures employed are ingeneral between −20° C. and +200° C., preferably between 0° C. and 120°C.

The process according to the invention is generally carried out underatmospheric pressure. However, it is also possible to work underincreased pressure, in general between 10 and 100 bar.

The reaction according to Process 6 is preferably carried out usingdiluents.

Suitable diluents are virtually all inert organic solvents. Theseinclude, preferably, aliphatic and aromatic, optionally halogenatedhydrocarbons, benzine, ligroin, benzene, toluene, xylene, methylenechloride, ethylene chloride, chloroform, carbon tetrachloride,chlorobenzene and o-dichlorobenzene, ethers such as diethyl and dibutylether, glycol dimethyl ether and diglycol dimethyl ether,tetrahydrofuran and dioxane, ketones such as acetone, methyl ethyl,methyl isopropyl and methyl isobutyl ketone, esters such as methylacetate and ethyl acetate, nitriles, for example acetonitrile andpropionitrile, amides, for example dimethylformamide, dimethylacetamideand N-methyl-pyrrolidone, and dimethyl sulphoxide, tetramethylenesulphone and hexamethylphosphoric triamide.

The reaction is carried out in the presence of inorganic or organicprotic acids. Examples of these which may be mentioned are:hydrochloric. acid, sulphuric acid, trifluoroacetic acid, acetic acid,formic acid.

The reaction is carried out at temperatures of between −20 and +50° C.,preferably at between −10 and +20° C., under atmospheric pressure orincreased pressure. Atmospheric pressure is preferably used.

The reaction according to Process 8 is preferably carried out usingdiluents.

Suitable diluents are virtually all inert organic solvents. Theseinclude, preferably, aliphatic and aromatic, optionally halogenatedhydrocarbons, benzine, ligroin, benzene, toluene, xylene, methylenechloride, ethylene chloride, chloroform, carbon tetrachloride,chlorobenzene and o-dichlorobenzene, ethers such as diethyl and dibutylether, glycol dimethyl ether and diglycol dimethyl ether,tetrahydrofuran and dioxane, ketones such as acetone, methyl ethyl,methyl isopropyl and methyl isobutyl ketone, esters such as methylacetate and ethyl acetate, nitrites, for example acetonitrile andpropionitrile, amides, for example dimethylformamide, dimethylacetamideand N-methyl-pyrrolidone, and dimethyl sulphoxide, tetramethylenesulphone and hexamethylphosphoric triamide.

The reaction is carried out in the presence of inorganic or organic acidacceptors.

Examples of these which may be mentioned are:

Alkali metal hydroxides, for example sodium hydroxide and potassiumhydroxide, alkaline earth metal hydroxides, for example calciumhydroxide, alkali metal carbonates and alcoholates such as sodiumcarbonate and potassium carbonate, sodium methylate or ethylate andpotassium methylate or ethylate, also aliphatic, aromatic orheterocyclic amines, for example triethylamine, pyridine,1,5-diazobicyclo-[4.3.0]-non-5-ene (DBN),1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU) and1,4-diazabicyclo-[2.2.2]-octane (DABCO), ethyl-diisopropylamine.

The reaction is carried out at temperatures of between 10 150° C.,preferably at between 20 to 100° C. at atmospheric pressure or increasedpressure. Atmospheric pressure is preferably used.

Process 11 is carried out as indicated above for the procedure ofProcess 6.

The process according to the invention described above under 12 iscarried out as indicated for Process 4.

Process 14 is carried out as indicated above for the procedure ofProcess 8.

Process 17 is carried out as indicated above for the procedure ofProcess 6.

Process 18 is carried out as indicated above for the procedure ofProcess 12.

Process 21 according to the invention is carried out in the presence ofa metal carbonate, or the amino acids of the formula (XII) are employedin the form of their salts, preferably alkali metal salts, particularlypreferably their caesium salts. It is preferred to employ alkali metalor alkaline earth metal carbonates, such as lithium carbonate, sodiumcarbonate, potassium carbonate, magnesium carbonate and calciumcarbonate.

Process 21 according to the invention is carried out using anaprotically polar organic solvent. These include, preferably, etherssuch as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether,diisobutyl ether, tetrahydrofuran and dioxane, ketones such as acetone,methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone and methylisobutyl ketone, esters such as methyl acetate and ethyl acetate,nitrites such as acetonitrile and propionitrile, amide such as dimethylformamide and dimethyl acetamide, and also N-methylpyrrolidone, dimethylsulphoxide, tetramethylene sulphone and hexamethylphosphoric triamide.

The reaction temperatures for Process 21 according to the invention canbe varied over a relatively wide range. The temperatures employed are ingeneral between −20° C. and +30° C., preferably between −5° C. and+10°C.

Process 21 according to the invention is generally carried out underatmospheric pressure. However it is also possible to work underincreased or reduced pressure of in general between 0.1 and 10 bar.

Process 22 is carried out as indicated for Process 21.

While being of favourable toxicity for warm-blooded creatures, theactive substances are suitable for controlling pathogenic endoparasiteswhich occur in humans and, in the keeping and rearing of animals, inlivestock, breeding stock, zoo animals, laboratory animals, animals forexperimentation and hobby animals. In this context they are activeagainst all or individual development stages of the pests, and againstresistant and normally sensitive species. The control of the pathogenicendoparasites is intended to reduce disease, deaths and reductions inyield (e.g. in the production of meat, milk, wool, hides, eggs, honeyetc.), so that the use of the active substance enables the keeping ofanimals to be more economic and more simple. The pathogenicendoparasites include cestodes, trematodes, nematodes, Acantocephala inparticular:

From the order of the Pseudophyllidea e.g.: Diphyllobothrium spp.,Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp.,Diphlogonoporus spp..

From the order of the Cyclophyllidea e.g.: Mesocestoides spp.,Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsaspp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaeniaspp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp.,Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp.,Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp.,Joyeuxiella spp., Diplopylidium spp..

From the subclass of the Monogenea e.g.: Gyrodactylus spp., Dactylogyrusspp., Polystoma spp..

From the subclass of the Digenea e.g.: Diplostomum spp.,Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp.,Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp.,Leucochloridium spp., Brachylaima spp., Echinostoma spp.,Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciolaspp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp.,Typhlocoelum spp., Paramphistomum spp., Calicophoron spp-, Cotylophoronspp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp.,Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonimusspp., Dicrocoelium spp., Eurytrema Bpp., Troglotrema spp., Paragonimusspp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchisspp. Metorchis spp., Heterophyes spp., Metagonimus spp..

From the order of the Enoplida e.g.: Trichuris spp., Capillaria spp.,Trichomosoides spp., Trichinella spp..

From the order of the Rhabditia e.g.: Micronema spp., Strongyloidesspp..

From the order of the Strongylida e.g.: Stronylus spp., Triodontophorusspp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp.,Cylindropharynx spp., Poteriostomum spp., Cyclococercus spp.,Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurusspp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalusspp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulusspp., Muellerius spp., protostronglyus spp., Neostrongylus spp.,Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp.,Elaphostrongylus spp. Parelaphostrongylus spp., Crenosoma spp.,Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp.,Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchusspp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirusspp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanusspp..

From the order of the Oxyurida e.g.: Oxyuris spp., Enterobius spp.,Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp..

From the order of the Ascaridia e.g.: Ascaris spp., Toxascaris spp.,Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp..

From the order of the Spirurida e.g.: Gnathostoma spp., Physalopteraspp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp.,Draschia spp., Dracunculus spp..

From the order of the Filariida e.g.: Stephanofilaria spp., Parafilariaspp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp.,Brugia spp., Wuchereria spp., Onchocerca spp..

From the order of the Gigantorhynchida e.g.: Filicollis spp.,Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp..

The livestock and breeding stock animals include mammals, for examplecattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys,rabbits, fallow deer, reindeer, fur animals, for example mink,chinchilla, racoon, birds, for example chickens, geese, turkeys, ducks,freshwater and salt-water fish, for example trout, carp, eels, reptiles,insects, for example honey bees, and silkworms.

Laboratory animals and those for experimentation include mice, rats,guinea-pigs, golden hamsters, dogs and cats.

Hobby animals include dogs and cats.

Administration can be carried out both prophylactically andtherapeuticaly.

The administration of the active substances is carried out, directly orin the form of suitable formulations, enterally, parenterally, dermally,nasally, by treating the surrounding area or with the aid of shapedarticles containing active substance, for example strips, plates, tapes,collars, ear-tags, limb bands, marking devices.

The enteral administration of the active substances is effected, forexample, orally in the form of powder, tablets, capsules, pastes,potions, granules, solutions suitable for oral administration,suspensions and emulsions, boli, medicated feed or drinking water. Thedermal application is effected, for example, by dipping, spraying orpouring-on and spotting-on. The parenteral administration is effected,for example, by injection (intramuscular, subcutaneous, intravenous,intraperitoneal) or by means of implants.

Suitable formulations are:

Solutions such as solutions for injection, oral solutions, concentratesfor oral administration after dilution, solutions for use on the skin orin body cavities, pour-on formulations, gels;

Emulsions and suspension for oral or dermal administration and forinjection; semi-solid formulations;

Formulations in which the active substance is processed in an ointmentbase or in an oil-in-water or water-in-oil emulsion base;

Solid formulations such as powders, premixes or concentrates, granules,pellets, tablets, boli, capsules; aerosols and inhalation products,shaped articles containing active substance.

Injection solutions are administered intravenously, intramuscularly andsubcutaneously.

Injection solutions are prepared by dissolving the active substance in asuitable solvent and adding, if appropriate, additives such assolubilizers, acids, bases, buffer salts, antioxidants, preservatives.The solutions are subjected to sterile filtration and placed incontainers.

Solvents which may be mentioned are: physiologically compatible solventssuch as water, alcohols such as ethanol, butanol, benzyl alcohol,glycerol, propylene glycol, polyethylene glycols, N-methyl-pyrrolidone,and mixtures thereof.

If appropriate, the active substances can also be dissolved inphysiologically compatible vegetable or synthetic oils suitable forinjection.

Solubilizers which may be mentioned are: solvents which promote thedissolution of the active substance in the principle solvent or preventits precipitation. Examples are polyvinyl pyrrolidone, polyoxyethylatedcastor oil, polyoxyethylated sorbitol esters.

Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoates,n-butanol.

Oral solutions are administered directly. Concentrates are administeredorally after prior dilution to the use concentration. Oral solutions andconcentrates are prepared as described above for the injectionsolutions, although sterile conditions can be dispensed with.

Solutions for use on the skin are applied in drops, painted on, rubbedin or sprayed on. These solutions are prepared as described above forthe injection solutions.

It may be advantageous to add thickeners during the preparation.Thickeners are: inorganic thickeners such as bentonites, colloidalsilica, aluminium monostearate, organic thickeners such as cellulosederivatives, polyvinyl alcohols and copolymers thereof, acrylates andmetacrylates.

Gels are applied to or painted onto the skin or introduced into bodycavities. Gels are prepared by the addition, to solutions which havebeen prepared as described for the injection solutions, of a quantity ofthickener which ensures that a clear mass of cream-like consistency isformed. The thickeners employed are the thickeners indicated above.

Pour-on formulations are poured or sprayed onto limited areas of theskin, the active substance penetrating the skin and acting systemically.

Pour-on. formulations are prepared by dissolving, suspending oremulsifying the active substance in suitable skin-compatible solvents orsolvent mixtures. If desired, further auxiliaries such as colorants,absorption-promoting substances, antioxidants, light stabilizers,adhesives are added.

Solvents which can be mentioned are: water, alkanols, glycols,polyethylene glycols, polypropylene glycols, glycerol, aromatic alcoholssuch as benzyl alcohol, phenylethanol, phenoxyethanol, esters such asethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkyleneglycol alkyl ethers such as -dipropylene glycol monomethyl ether,diethylene glycol mono-butyl ether, ketones such as acetone, methylethylketone, aromatic and/or aliphatic hydrocarbons, vegetable or syntheticoils, DMF, dimethylacetamide, N-methyl-pyrrolidone,2,2-dimethyl-4-oxy-methylene-1,3-dioxolane.

Colorants are all colorants permitted for use with animals, and may bedissolved or suspended.

Absorption-promoting substances are, for example, DMSO, spreading oilssuch as isopropyl myristate, dipropylene glycol pelargonate, siliconeoils, fatty acid esters, triglycerides, fatty alcohols.

Antioxidants are sulphites or metabisulphites such as potassiummetabisulphite, ascorbic acid, butyl hydroxy-toluene,butylhydroxyanisole, tocopherol.

Light stabilizers are, for example, Novantisol acid.

Adhesives are, for example, cellulose derivatives, starch derivatives,polyacrylates, natural polymers such as alginates, gelatin.

Emulsions can be administered orally, dermally or as injections.

Emulsions are either of the water-in-oil type or of the oil-in-watertype.

They are prepared by dissolving the active substance either in thehydrophobic or in the hydrophillic phase and homogenizing this phase,with the aid of suitable emulsifiers and, if appropriate, otherauxiliaries such as colorants, absorption-promoting substances,preservatives, antioxidants, light stabilizers, viscosity-increasingsubstances, with the solvent of the other phase.

As the hydrophobic phase (oils) there may be mentioned: paraffin oils,silicone oils, natural vegetable oils such as sesame oil, almond oil,castor oil, synthetic triglycerides such as caprylic/capric acidbigylceride, a triglyceride mixture with plant fatty acids of chainlength C₈₋₁₂ or other specially selected natural fatty is acids, partialglyceride mixtures of saturated or unsaturated fatty acids, ifappropriate together with fatty acids containing hydroxyl groups, mono-and diglycerides of C₈/C₁₀ fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, hexyllaurate, dipropylene glycol pelargonate, esters of a branched fatty acidof medium chain length with saturated fatty alcohols of chain lengthC₁₆-C₁₈, isopropyl myristate, isopropyl palmitate, caprylic/capric acidesters of saturated fatty alcohols of chain length C₁₂-C₁₈, isopropylstearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate,wax-like fatty acid esters such as synthetic duck oil-gland fat, dibutylphthalate, diisopropyl adipate, ester mixtures related to the latter,etc.

Fatty alcohols such as isotridecyl alcohol, 2-octyl-dodecanol,cetylstearyl alcohol, oleyl alcohol.

Fatty acids, for example oleic acid, and mixtures thereof.

As the hydrophillic phase there may be mentioned: water, alcohols, forexample propylene glycol, glycerol, sorbitol, and mixtures thereof.

Emulsifiers which may be mentioned are: nonionic surfactants, e.g.polyoxyethylated castor oil, polyoxyethylated sorbitol monooleate,sorbitol monostearate, glycerol monostearate, polyoxyethyl stearate,alkylphenol polyglycol ether;

ampholytic surfactants such as di-Na-N-lauryl-β-iminodipropionate orlecithin;

anionic surfactants such as Na-lauryl sulphate, fatty alcohol ethersulphates, mono/dialkylpolyglycol ether orthophosphoric acid estermonoethanol amine salt;

cationic surfactants such as cetyltrimethylammonium chloride.

Further auxiliaries which may be mentioned are: viscosity-increasing andemulsion-stabilizing substances such as carboxymethyl cellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates,alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol,copolymers of methyl vinyl ether and maleic anhydride, polyethyleneglycols, waxes, colloidal silica, or mixtures of the substances listed.

Suspensions can be administered orally, dermally or by injection. Theyare prepared by suspending the active substance in a carrier liquid,with the optional addition of further auxiliaries such as wettingagents, colorants, absorption-promoting substances, preservatives,antioxidants light stabilizers.

Carrier liquids which may be mentioned are all homogeneous solvents andsolvent mixtures.

Wetting agents (dispersants) which may be mentioned are the surfactantsgiven above.

Further auxiliaries which may be mentioned are those given above.

Semi-solid formulations may be administered orally or dermally. Theydiffer from the above-described suspensions and emulsions only in theirhigher viscosity.

For the preparation of solid formulations, the active substance is mixedwith suitable carrier substances with the optional addition ofauxiliaries, and brought into the desired form.

Carrier substances which may be mentioned are all physiologicallycompatible solid inert substances. Suitable substances are inorganic andorganic substances. Examples of inorganic substances are common salt,carbonates such as calcium carbonate, hydrogen carbonates, aluminiumoxides, silicic acids, argillaceous earths, precipitated or colloidalsilicon dioxide, phosphates.

Examples of organic substances are sugar, cellulose, nutrients andfeedstuffs such as milk powder, animal meals, corn meals and wholemeals,starches.

Auxiliaries are preservatives, antioxidants, colorants, which havealready been listed above.

Other suitable auxiliaries are lubricants and glidants, for examplemagnesium stearate, stearic acid, talc, bentonites,disintegration-promoting substances such as starch or crosslinkedpolyvinylpyrrolidone, binders, for example starch, gelatin or linearpolyvinylpyrrolidone, and dry binders such as microcrystallinecellulose.

The active substances can also be present in the formulations as amixture with synergists or with other active substances which actagainst pathogenic endoparasites. Examples of such active substances areL-2,3,5,6-tetra-hydro-6-phenyl-imidazothiazole, benzimidazolecarbamates, praziquantel, pyrantel, febantel.

Ready-to-use formulations contain the active substance in concentrationsof from 10 ppm-20 per cent by weight, preferably from 0.1-10 per cent byweight.

Formulations which are diluted prior to use contain the active substancein concentrations of from 0.5-90 per cent by weight, preferably from 5to 50 per cent by weight.

In general it has proven advantageous to administer amounts of fromapproximately 1 to approximately 100 mg of active substance per kg ofbody weight per day in order to achieve effective results.

EXAMPLE A In Vivo Nematode Test

Haemonchus contortus/sheep

Sheep experimentally infected with Haemonchus contortus were treatedafter the end of the pre-patency period of the parasites. The activecompounds were administered orally as pure active compound in gelatincapsules.

The degree of effectiveness is determined by quantitatively counting theworm eggs excreted with the faeces, before and after treatment.

Complete cessation of the excretion of eggs after the treatment meansthat the worms have been expelled or are severely damaged that they canno longer produce any eggs (effective dose).

The active substances tested and the active doses are evident from thefollowing table:

Active substance Effective dose Example No. in mg/kg 1 5 2 5 3 5

The preparation of the active substances according to the invention isevident from the following examples.

PREPARATION EXAMPLES 1. Preparation of the Compounds of the Formula (I)According to Process 2

BOP-Cl (0.124 mmol) was added at 0° C. to a solution of compound II(0.104 mmol) and Hünig base (0.258 mmol) in dichloromethane (100 ml) andthe mixture was subsequently stirred for 24 hours at room temperature.After this time, the same quantities of BOP-Cl and base were added, andthe mixture was stirred for a further 24 hours. The solution was washedtwice with saturated sodium hydrogen carbonate solution, dried oversodium sulphate and concentrated. The residue was purified by columnchromatography using the eluent cyclohexane-ethyl acetate 2:1.

Compounds of the formula (I) were obtained in which the substituentshave the following meaning:

TABLE 1 Ex. FAB-MS No. R¹ R¹² R⁹ R⁸ R⁷ R⁶ R⁵ R⁴ R³ R¹⁰ R¹¹ R² m/Z (%) 1Et Et Me i-Bu Bn i-Bu Me i-Bu Bn i-Bu Et Et 1027 (100, (M + Na)+), 1005(14, (M + H)⁺) 2 Propyl Propyl ″ ″ ″ ″ ″ ″ ″ ″ Propyl Propyl 1083 (100,(M + Na)⁺), 1061 (64, (M + H)⁺) 3 i-propyl i-propyl ″ ″ ″ ″ ″ ″ ″ ″i-Propyl i-Propyl 1061 (45, (M + H)⁺) 4 Phenyl Phenyl ″ ″ ″ ″ ″ ″ ″ ″ MeMe 5 Et Et ″ ″ ″ ″ ″ ″ ″ ″ Me Me 6 Propyl Propyl ″ ″ ″ ″ ″ ″ ″ ″ Me Me 7Et Et ″ ″ 2-Cl-Bn ″ ″ ″ 2-Cl-Bn ″ Me Me 8 Et Et ″ ″ 3-Cl-Bn ″ ″ ″3-Cl-Bn ″ Et Et 9 Propyl i-Propyl ″ ″ 4-Cl-Bn ″ ″ ″ 4-Cl-Bn ″ Propyli-Propyl 10 Propyl i-Propyl ″ ″ Bn ″ ″ ″ Bn ″ Propyl i-Propyl Me =Methyl Et = Ethyl Bu = Butyl Bn = Benzyl

2. Preparation of the Compounds of the Formula (II) According to Process4

A solution of a compound of the formula III (1.222 mmol) in ethanol (50ml) was hydrogenated in S the presence of Pd(OH)₂/C (20%; 200 mg) untilhydrogen uptake had finished (about 2 hours). After the catalyst hadbeen filtered off, 92% compound of the formula (II) was obtained whichwas reacted further without additional purification.

In accordance with this procedure, compounds of the formula (II) wereobtained in which the substituents have the following meaning:

TABLE 2 Ex. No. R¹ R¹² R⁹ R⁸ R⁷ R⁶ R⁵ R⁴ R³ R¹⁰ R¹¹ R² 1 Et Et Me i-BuBn i-Bu Me i-Bu Bn i-Bu Et Et 2 Propyl Propyl ″ ″ ″ ″ ″ ″ ″ ″ PropylPropyl 3 i-Propyl i-Propyl ″ ″ ″ ″ ″ ″ ″ ″ i-Propyl i-Propyl 4 Me Me ″s-Bu ″ s-Bu ″ s-Bu ″ s-Bu Me Me 5 Me Me ″ i-Pr ″ i-Pr ″ i-Pr ″ i-Pr MeMe 6 Me Me ″ Bn ″ Bn ″ Bn ″ Bn Me Me 7 Me Me ″ i-Bu 2-Cl-Bn i-Bu ″ i-Bu2-Cl-Bn i-Bu Me Me 8 Me Me ″ ″ 3-Cl-Bn ″ ″ ″ 3-Cl-Bn ″ Me Me 9 Me Me ″ ″4-Cl-Bn ″ ″ ″ 4-Cl-Bn ″ Me Me 10 Propyl i-Propyl ″ ″ Bn ″ ″ ″ Bn ″Propyl i-Propyl Me = Methyl Et = Ethyl Bu = Butyl Pr = Propyl Bn =Benzyl

3. Preparation of the Compounds of the Formula (III) According toProcess 6

HCl gas was passed into a solution of the tert.-butyl ester of theformula (IV) (1,609 mmol) in dichloromethane (40 ml) for 1.5 h at 0° C.The mixture was then heated to room temperature and subsequently stirredfor 12 h. The solution was concentrated on a rotary evaporator and driedunder a high vacuum. The residue was reacted without furtherpurification.

In accordance with this procedure, compounds of the formula (III) wereobtained in which the substituents have the following meaning:

TABLE 3 No. R¹ R¹² R⁹ R⁸ R⁷ R⁶ R⁵ R⁴ R³ R¹⁰ R¹¹ R² A B 21 Et Et Me i-BuBn i-Bu Me i-Bu Bn i-Bu Et Et Bn OH 22 Propyl Propyl ″ ″ ″ ″ ″ ″ ″ ″Propyl Propyl ″ ″ 23 i-Propyl i-Propyl ″ ″ ″ ″ ″ ″ ″ ″ i-Propyl i-Propyl″ ″ 24 Phenyl Phenyl ″ ″ ″ ″ ″ ″ ″ ″ Me Me ″ ″ 25 Et Et ″ ″ ″ ″ ″ ″ ″ ″Me Me ″ ″ 26 Propyl Propyl ″ ″ ″ ″ ″ ″ ″ ″ Me Me ″ ″ 27 i-Propyli-Propyl ″ ″ ″ ″ ″ ″ ″ ″ Me Me ″ ″ 28 Et Propyl ″ ″ ″ ″ ″ ″ ″ ″ EtPropyl ″ ″ 29 Et i-Propyl ″ ″ ″ ″ ″ ″ ″ ″ Et i-Propyl ″ ″ 30 Propyli-Propyl ″ ″ ″ ″ ″ ″ ″ ″ Propyl i-Propyl ″ ″

4. Preparation of the Compounds of the Formula (IV) According to Process8

Tetradepsipeptides of the formula (VI) (2.52 mmol) and of the formula V(2.52 mmol) were initially introduced in dichloromethane (15 ml), thesolution was cooled to 0° C., and ethyldiisopropylamine (0.912 mmol) andBOP-Cl (0.438 mmol) were added. The mixture was subsequently stirred for1 hour at 0° C. and for 1.5 hours at room temperature, then diluted withdichloromethane, washed twice with a little water, dried over sodiumsulphate and concentrated. The residue was purified on silica gel withthe eluent cyclohexane-t-BuOMe=2:1.

In accordance with this procedure, compounds of the formula (IV) wereobtained in which the substituents have the following meaning.

TABLE 4 No. R¹ R¹² R⁹ R⁸ R⁷ R⁶ R⁵ R⁴ R³ R¹⁰ R¹¹ R² A B 31 Et Et Me i-BuBn i-Bu Me i-Bu Bn i-Bu Et Et Bn t-BuO 32 Propyl Propyl ″ ″ ″ ″ ″ ″ ″ ″Propyl Propyl ″ ″ 33 i-Propyl i-Propyl ″ ″ ″ ″ ″ ″ ″ ″ i-Propyl i-Propyl″ ″ 34 Phenyl Phenyl ″ ″ ″ ″ ″ ″ ″ ″ Me Me ″ ″ 35 Et Et ″ ″ ″ ″ ″ ″ ″ ″Me Me ″ ″ 36 Propyl Propyl ″ ″ ″ ″ ″ ″ ″ ″ Me Me ″ ″ 37 i-Propyli-Propyl ″ ″ ″ ″ ″ ″ ″ ″ Me Me ″ ″ 38 Et Propyl ″ ″ ″ ″ ″ ″ ″ ″ EtPropyl ″ ″ 39 Et i-Propyl ″ ″ ″ ″ ″ ″ ″ ″ Et i-Propyl ″ ″ 40 Propyli-Propyl ″ ″ ″ ″ ″ ″ ″ ″ Propyl i-Propyl ″ ″

5. Preparation of the Compounds of the Formula (V) According to Process11

HCl gas was passed into a solution of the tetradepsipeptide with theformula (VII) (2,848 mmol) in dichloromethane (50 ml) for 2 h at 0° C.

The mixture was subsequently stirred at room temperature for 8 hours,concentrated and dried under a high vacuum. The residue was employedwithout further purification.

In accordance with this procedure, the following compounds of theformula (V) were obtained in which the substituents have the followingmeaning:

TABLE 5 No. R¹ R¹² R⁹ R⁸ R⁷ R¹⁰ A Z 41 Et Et Me i-Bu Bn i-Bu Bn OH 42Propyl Propyl ″ ″ ″ ″ ″ ″ 43 i-Propyl i-Propyl ″ ″ ″ ″ ″ ″ 44 PhenylPhenyl ″ ″ ″ ″ ″ ″ 45 Et Propyl ″ ″ ″ ″ ″ ″ 46 Et i-Propyl ″ ″ ″ ″ ″ ″47 Propyl i-Propyl ″ ″ ″ ″ ″ ″

6. Preparation of the Compounds of the Formula (VI) According to Process12

Tetradepsipeptides of the formula (VII) (9.53 mmol) were dissolved inethanol (37 ml), 0.6 g of Pd(OH)₂/C (20%) was added, and the mixture washydrogenated at room temperature until hydrogen uptake had finished.After the catalyst had been filtered off and the solvent had beenconcentrated, the residue was separated by column chromatography oversilica gel with the eluent BuOMe-cyclohexane-ethanol=1:1:0.5.

The compounds of the formula (VI) in which the substituents have thefollowing meaning were obtained analogously:

TABLE 6 No. R¹ R¹² R⁹ R⁸ R⁷ R¹⁰ D B 48 Et Et Me i-Bu Bn i-Bu H O t-Bu 49Propyl Propyl ″ ″ ″ ″ ″ ″ 50 i-Propyl i-Propyl ″ ″ ″ ″ ″ ″ 51 PhenylPhenyl ″ ″ ″ ″ ″ ″ 52 Et Propyl ″ ″ ″ ″ ″ ″ 53 Et i-Propyl ″ ″ ″ ″ ″ ″54 Propyl i-Propyl ″ ″ ″ ″ ″ ″

7. Preparation of the Compounds of the Formula (VII) According toProcess 14

Diisopropylethylamine (57.3 mmol) and BOP-Cl (29.8 mmol) were added to asolution, cooled to 0° C., of the didepsipeptide of the formula (IX)(22.9 mmol) and of the didepsipeptide of the formula (VIII) (27.5 mmol)in dichloromethane (80 ml), and the mixture was stirred for 1 hour at 0°C. and for 1 hour at room temperature. After the precipitate had beenfiltered off, the solution was diluted with dichloromethane, washedthree times with a little water, dried over sodium sulphate andconcentrated. The residue was separated on silica gel with the eluentcyclohexane-ethyl acetate=15:1.

In accordance with this procedure, the compounds of the formula (VII)were obtained in which the substituents have the following meaning:

TABLE 7 No. R¹ R¹² R⁹ R⁸ R⁷ R¹⁰ A C 55 Et Et Me i-Bu Bn i-Bu H O t-Bu 56Propyl Propyl ″ ″ ″ ″ ″ ″ 57 i-Propyl i-Propyl ″ ″ ″ ″ ″ ″ 58 PhenylPhenyl ″ ″ ″ ″ ″ ″ 59 Et Propyl ″ ″ ″ ″ ″ ″ 60 Et i-Propyl ″ ″ ″ ″ ″ ″61 Propyl i-Propyl ″ ″ ″ ″ ″ ″

8. Preparation of the Compounds of the Formula (VIII) According toProcess 17

HCl gas was passed into a solution of the didepsipeptide of the formula(X) (46.0 mmol) in dichloromethane (470 mml) at 0° C. for 2 hours. Thereaction solution was heated slowly and stirred overnight at roomtemperature. It was then concentrated, two portions (each 150 ml) ofdichloromethane were added, and the mixture was again concentrated anddried under a high vacuum. The residue was dissolved in water and addeddropwise to a suspension of a basic ion exchanger (16.7 g) in 50 ml ofwater, and the mixture was stirred for 3 hours, filtered andconcentrated. After drying under a high vacuum, an amorphous powder wasobtained which was reacted without further purification.

In accordance with this procedure, the compounds of the formula (VIII)were obtained in which the substituents have the following meaning:

TABLE 8 No. R¹ R⁹ R¹⁰ A Z 69 Et Me i-Bu Bn OH 70 Propyl Me i-Bu Bn OH 71i-Propyl Me i-Bu Bn OH 72 Phenyl Me i-Bu Bn OH

9. Preparation of the Compounds of Formula (IX) According to Process 18

2.91 g of Pd(OH)₂/C (20%) were added to a solution of the didepsipeptideof the formula (XI) (60.0 mmol) in 163 ml of ethanol, and the mixturewas hydrogenated for 6 hours at room temperature. It was then filtered,washed with ethanol and concentrated in vacuo. The residue was separatedon silica gel with the eluent cyclohexane-ethyl acetate=3:1.

In accordance with this procedure, the compounds of the formula (IX)were obtained in which the substituents have the following meaning:

TABLE 9 No. R² R⁸ R⁷ D B 73 Et i-Bu Bn H t-BuO 74 Propyl i-Bu Bn H t-BuO75 i-Propyl i-Bu Bn H t-BuO 76 Phenyl i-Bu Bn H t-BuO

10. Preparation of the Compounds of the Formula (X) According to Process21

The chlorocarboxylic acid of the formula (XIII) (0.212 mol) was added tothe caesium salt of the formula (XII) initially introduced in 530 ml ofdimethyl sulphoxide at room temperature. The mixture was stirred for 20hours at room temperature, poured into saturated sodium chloridesolution and extracted four times with ethyl acetate. The combinedorganic extracts were washed once with a little water, dried over sodiumsulphate and concentrated. The residue was purified by columnchromatography with the eluent cyclohexane-ethyl acetate=60:1.

In accordance with this procedure, the compounds of the formula (X) wereobtained in which the substituents have the following meaning:

TABLE 10 No. R¹ R⁹ R¹⁰ A Z 77 Et Me I-Bu Bn t-BuO 78 Propyl Me I-Bu Bnt-BuO 79 i-Propyl Me I-Bu Bn t-BuO 80 Phenyl Me I-Bu Bn t-BuO

11. Preparation of the Compounds of the Formula (XI) According toProcess 22

The amino acid of the formula (XIV) (0.212 mol) was dissolved in 1000 mlof ethanol and 100 ml of water, a 20% strength caesium carbonatesolution (200 ml) was added, and the mixture was stirred for 5 hours atroom temperature. It was then concentrated, co-distilled twice with 250ml of DMF each time, and dried overnight at 80° C. under a high vacuum.0.212 mol of this caesium salt were initially introduced into 530 ml ofdimethyl sulphoxide, 0.212 mol of the chlorocarboxylic acid of theformula (XV) was added at room temperature, and the mixture was stirredfor 20 hours at room temperature. The solution was poured into saturatedsodium chloride solution, extracted four times with ethyl acetate, andthe extracts were dried over sodium sulphate and concentrated. Theresidue was purified by column chromatography with the eluentcyclohexane-ethyl acetate=100:1.

Analogously, the compounds of the formula (XI) were obtained in whichthe substituents have the following meaning:

TABLE 11 No. R² R⁸ R⁷ D B 81 Et i-Bu Bn Bn t-BuO 82 Propyl i-Bu Bn Bnt-BuO 83 i-Propyl i-Bu Bn Bn t-BuO 84 Phenyl i-Bu Bn Bn t-BuO

What is claimed is:
 1. A compound of the formula

in which R¹ is C₂-C₄-alkyl or phenyl, R² is C₁₋₄-alkyl 2, R³ is hydrogenor phenyl-(C₁₋₄-alkyl) which is optionally substituted by halogen ornitro, R⁴ is hydrogen or C₁₋₅-alkyl, R⁵ is hydrogen or C₁₋₅-alkyl, R⁶ ishydrogen or C₁₋₅-alkyl, R⁷ is hydrogen or phenyl-(C₁₋₄-alkyl) which isoptionally substituted by halogen or nitro, R⁸ is hydrogen orC₁₋₅-alkyl, R⁹ is hydrogen or C₁₋₅-alkyl, R¹⁰ is hydrogen or C₁₋₅-alkyl,R¹¹ is C₁₋₄-alkyl, and R¹² is C₂₋₄-alkyl or phenyl.
 2. A compoundaccording to claim 1, wherein such compound is


3. A compound according to claim 1, wherein such compound is


4. A compound according to claim 1, wherein such compound is


5. An endoparasiticidal composition comprising an endoparasiticidallyeffective amount of a compound according to claim 1 and a diluent.
 6. Amethod of combating endoparasites which comprises applying to suchendoparasites or to an endoparasite habitat an endoparasiticidallyeffective amount of a compound according to claim 2.